Background Biologics are very effective to autoimmune diseases including rheumatoid arthritis and ankylosing spondylitis, but could cause infectious diseases as adverse effects. Human T-lymphotropic virus type-I (HTLV-I) is a retrovirus that infects 10 to 20 million people worldwide (1). The virus is associated with severe diseases, such as adult T-cell leukemia/lymphoma and HTLV-I-associated myelopathy (HAM). It is unknown if HTLV-I proliferates when biologics including TNF inhibitors (TNFi) are used.
Objectives We evaluated effects of TNFi to HTLV-I infected cells regarding cytokine profiles, TNF receptor (TNFR), mRNA of associated proteins, proviral load (PVL) and apoptosis.
Methods We used an HTLV-I infected cell line named HCT-5, which is derived from cells in spinal fluid of a patient with HAM. Multiplex cytokine/chemokine bead assays, cytokine levels assessed by enzyme-linked immunosorbent assays (ELISA), fluorescence activated cell sorting (FACS) analysis of TNFR, immunofluorescence staining of GAG, which is a HTLV-1 structural protein, quantitative reverse transcription PCR for Tax (2) and HTLV-I bZIP factor (HBZ) (3), which are needed for immortalization and proliferation of HTLV-I infected cells respectively, HTLV-I PVL (4), and apoptotic ladder detection were performed. We also used Jurkat as a control cell line.
Results Multiplex cytokine/chemokine bead assays showed supernatants of HCT-5 without any stimuli had time-dependent elevation of IL-6, TNF-alpha, RANTES and ICAM-1. Supernatants of HCT-5 treated with infliximab (IFX), adalimumab (ADA), etanercept (ETN), golimumab (GLM) and certolizumab pegol (CZP) assessed by ELISA showed no differences in levels of these molecules compared to that of HCT-5 with phosphate buffered saline (PBS). In FACS analysis, except for TNFR 2 with ETN, expressions of TNFR 1 and TNFR 2 with each TNFi did not differ from PBS. TNFR 2 declined and internalization of TNFR 2 was detected in HCT-5 with ETN. There was no differences in levels of mRNA of Tax (Figure A, PBGD: house keeping gene) and HBZ (Figure B) with TNFi compared to that with PBS. PVL were also not changed (Figure C, CTR: without any reagents). Immunofluorescence staining of GAG showed no differences between each TNFi and PBS. DNA ladder was not detected in any TNFi and PBS.
Conclusions In vitro, TNFi did not affect the cytokine profiles, TNFR 1, mRNA of associated proteins, proviral load and apoptosis of HCT-5. Only ETN caused internalization of TNFR 2.
de The G, Bomford R. An HTLV-I vaccine: why, how, for whom? AIDS Res Hum Retroviruses. 1993;9:381–6.
Harhaj EW, Harhaj NS. Mechanisms of persistent NF-kappaB activation by HTLV-I tax. IUBMB Life. 2005;57:83–91.
Matsuoka M, Jeang KT. Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy. Oncogene. 2011;30:1379–89.
Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81.
Disclosure of Interest None declared